Pharmacovigilance in real life may 12

Pharmacovigilance in Real Life

An Industry Perspective

Barry ArnoldEU Qualified Person for PharmacovigilanceAstraZeneca

Global Medicines Development | Chief Medical OfficePV in real life | May 2012

Content of presentation

• Why undertake pharmacovigilance?• Pharmacovigilance processes• Impact of new EU legislation

Why Undertake Pharmacovigilance?


Historical Milestones

……. 50 years ago


Milestones

1961 Thalidomide: phocomelia

1962 High dose isoprenaline: asthma deaths

1970 High dose oestrogen oral contraceptives: thromboembolic disease

1971 Diethylstilboestrol: vaginal carcinoma in daughters

1974 Pertussis vaccine: encephalopathy

1975 Practolol: oculomucocutaneous syndrome

1979 Triazolam (Halcion): psychiatric symptoms

1982 Benoxaprofen (Opren): hepatotoxicity & photosensitivity in elderly patients

1993 Fialuridine: hepatotoxicity

1993 Sorivudine: fatal neutropenia (interaction with 5FU)

1996 3rd generation oral contraceptives: venous thromboembolism

1997 Troglitazone (Rezulin): hepatoxicity


Milestones cont’d

1998 Seldane (terfenadine) Posicor (mibefradil)Duract (bromphenac) ‘Fen-phen’ (fenfluramine/phentermine)

1999 Hismanal (astemizole) Raxar (grepafloxacin

2000 Prepulsid (cisapride) Lotronex (alosetron)

2001 Baycol (cerivastatin)

2004 Vioxx (rofecoxib)

2005 Tysabri (natalizumab) Bextra (valdecoxib)

2007 Avandia (rosiglitazone)

2008/09 Selective Serotonin Reuptake Inhibitors

2008/12 Proton Pump Inhibitors

2012 Implementation of new EU legislation


Why undertake pharmacovigilance?

• To quickly identify, evaluate and communicate potential risks to patients

- Optimise prescribing information & patient information- Comply with regulations, and satisfy regulators- Reduce the risk of product liability


“Show me a drug without side-effects and I shall show you a drug

that does not work”

Dunlop

The Pharmacovigilance Process


What is Pharmacovigilance?

• The science & activities relating to the detection, assessment, understanding and prevention of adverse events or any other drug-related problems (WHO).

• The ongoing process by which we conduct a systematic evaluation of safety data in order to anticipate, identify, respond to and communicate about safety issues throughout the life-cycle of pharmaceutical products (Anon).


Pharmacovigilance has no boundaries


AstraZeneca Patient Safety

VP, Clinical Development

VP, Patient Safety

Safety Science

UK Sweden

Executive DirectorGlobal Development

Processes & Standards Team

USA

Tata Consulting Services SupportSafety Surveillance

QPPV

Chief Medical Officer

Epidemiology


Role of AstraZeneca Patient Safety

• Provide integrated strategic safety expertise to clinical development programmes

• Conduct active pharmacovigilance with rapid identification and analysis of safety signals; define the safety profile of AZ products and drive patient risk management

• Deliver high quality product safety information throughout the product life cycle

• Ensure regulatory compliance


EU Qualified Person for Pharmacovigilance

• QPPV responsible for:- Collection and collation of all suspected ADRs; to be

accessible at least at one point within the EU- Preparation of expedited and periodic safety reports, and

reports on post-authorisation safety studies- Ongoing pharmacovigilance evaluation- Responding to requests for information from regulatory

authorities- Provision of additional information upon request from

Competent Authorities relevant to evaluation of benefit-risk- Notifying changes to benefit-risk profile- QC/QA of the pharmacovigilance system


Pharmacovigilance Process

LiteratureReportsSpontaneous

Reports

Study &PMS Data

RegulatoryReports

Data InData Review& Evaluation

DatabaseEntry Action

Follow-up Data

Output

RegulatoryReports

SafetyUpdates

Response to Enquiry

SignalGeneration

Healthcare ProfessionalConsumerLawyerRegulatory Authority


Reporter/Investigator

AZ staffMC/CRO

Data Entry Site

Regulatory Authorities

Marketing Companies

JASPER

Queries Queries

AstraZeneca Case Handling Process


Expedited ADR Reports

• Clinical development products- 7 days: fatal/life-threatening unexpected ADRs- 15 days: other serious unexpected ADRs

• Marketed products- 15 days: serious ADRs

• All products: other important safety information to be submitted without delay

• AZ generates reports for all serious ADRs ® submitted individually (selected by computer algorithm)


PSURs

• Provided to EU regulatory authorities:- 6 monthly for first 2 years after marketing- Annually for subsequent 2 years- Thereafter at 3 yearly intervals

• Presentation, analysis and evaluation of new or changing safety data received during period of PSUR

• Reassure all relevant regulatory authorities that:- Safety surveillance activities are appropriate- Core Data Sheet (with any proposed amendments)

accurately reflects the benefit‑risk profile of the product and its safe use in clinical practice


Safety Surveillance

• Proactive detection of safety signals- Optimises protection of patients- Meets regulatory expectations

• Safety signals arise from numerous sources e.g. individual case reports, published literature, clinical studies, regulatory authorities, etc

• Manual review supported by automated quantitative signal detection (disproportionality analyses) of in-house and external safety databases

• Cross-functional peer review process for signal evaluation


Risk Management Plans

• Risk Management Plan: A plan identifying the risks associated with a medicinal product, methods to further clarify the safety profile of a product, and ways to minimise risk to individual patients in clinical use

Safety Specification Pharmacovigilance Plans Risk Minimisation Activities

• Each RMP should be unique for the product under consideration


Risk management

A risk that is recognised, quantified and publicised is a risk accepted

A lesser risk, as a surprise can kill a drug

Anon


Risk Management Plans

• Alosetron • Cisapride • Cerivastatin • Felbamate• Sertindole

• Sibutramine• Soruvidine • Terfenadine• Troglitazone

Could these products have avoided withdrawal if they had effective risk

management plans at launch?

Impact of EU Pharmacovigilance

Legislation


Rationale for new legislation

In light of experience and following an assessment made of the EU pharmacovigilance system……made by the Commission, it has become clear that new measures are necessary to improve how the EU rules operate on the pharmacovigilance of medicinal products. Today’s proposals seek to change the existing EU legislation on pharmacovigilance (…). They aim at strengthening and rationalizing the EU pharmacovigilance system, with the overall objectives of better protecting public health, ensuring proper functioning of the internal market and simplifying the current procedures.


EU Pharmacovigilance Legislation

• Objectives Strengthen & rationalise EU pharmacovigilance system Greater transparency

• Published in Official Journal of EU (31 December 2010) Regulation (EU) 1235/2010, amending Regulation (EC)

726/2004 Directive 2010/84/EU, amending Directive 2001/83/EC New provisions will apply from July 2012/January 2013/2015

• Further details to be provided during 2012 European Commission ‘Implementing Regulation’ European Medicines Agency guidelines (Good Vigilance

Practice & Post-Authorisation Efficacy Studies)


Implementing Regulation

1. Pharmacovigilance system master file

2. Quality system for performance of PV activities

3. Monitoring of data in EudraVigilance

4. Use of terminology

5. Transmission of suspected adverse reactions

6. Risk management plans

7. Periodic safety update reports

8. Post-authorisation safety studies

9. Final provisions

Annexes I-III


Good Vigilance Practice Guideline

• Principles to be applicable to MAH PV systems globally• To apply across all member states

Any deviation from the guideline to be fully justified

• 15 modules + 5 annexes: will be several hundred pages long!

• Draft guidelines being issued in ‘waves’ for public consultation- Wave I – February 2012; 8 weeks consultation period- Wave II – to be determined


Principles for Good Vigilance Practice

• Higher management to lead implementation of the quality system and motivation for all staff in relation to quality objectives

• All persons within the organisation to be involved in and support the pharmacovigilance system on the basis of task ownership and responsibility; all persons should engage in continuous quality improvement

• Resources and tasks to be organised to support proactive, risk-proportionate, continuous and integrated conduct of pharmacovigilance

• All available evidence on benefit-risk of medicinal products should be sought; all relevant aspects, which could impact on benefit-risk and the use of a product, should be considered for decision-making


Summary of the Pharmacovigilance System

• Each MAA to include the following information:- Proof that the applicant has the services of a QPPV - Member State where the QPPV resides & works- Contact details for the QPPV- Statement signed by the applicant to the effect that the

applicant has the necessary means to fulfill its pharmacovigilance responsibilities

- Location of the pharmacovigilance system master file

• Amendment to this information will require a ‘variation’


Supervisory authority

• The ‘supervisory authority’ for pharmacovigilance will be the competent authority of the Member State in which the MAH pharmacovigilance system master file is located

• Responsible for verifying on behalf of the Community that the MAH meets pharmacovigilance requirements i.e. through PV inspections


European Medicines Web-Portal

• EMA to establish European medicines web-portal ® increase transparency of pharmacovigilance issues

• Public access to: List of CHMP, CMDh & PRAC members PRAC meeting agendas & minutes List of products subject to ‘additional monitoring’ List of locations of MAH master files & contact information for

pharmacovigilance enquiries PSUR reference dates, frequency of submission, and PSUR

assessment reports (conclusions) Summaries of RMPs PASS protocols & abstracts of results Information on ‘urgent’ EU procedures


Impact on workload

• Increased workload associated with the following:- Quality system- PV System Master File- Data management- Signal management- ICSR reporting- Assessment of off-label use- Risk management plans- Effectiveness of risk minimisation- Post-authorisation studies

• Periodic reports: depends what type of product the company markets

• Increased transparency: difficult to predict


Future Expectations

• Changes to regulatory requirements- EU legislation: Strengthening, transparency and rationalisation of

pharmacovigilance requirements- Clinical Trials Directive: strengthen or rationalise?

• Increased involvement of patients in pharmacovigilance- Direct notification of AEs- Public access to safety data and reports

• Utilisation of electronic healthcare records for ‘real-time’ pharmacovigilance?

• Development of methods for risk minimisation, and assessment of their effectiveness?

• Increased litigation & media attention to drug safety?

Pharmacovigilance in real life may 12

Health & Medicine

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